F
IPR002289

Gamma-aminobutyric-acid A receptor, beta subunit

InterPro entry
Short nameGABAAb_rcpt
Overlapping
homologous
superfamilies
 
family relationships

Description

Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses
[6, 7]
. Five of these ion channel receptor families have been shown to form a sequence-related superfamily:


 * Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits
[2]
.
 * Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits
[3]
.
 * Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known
[13]
.
 * Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7)
[5]
.
 * Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate)
[1]
.


These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence
[6, 7]
.

Gamma-aminobutyric acid type A (GABAA) receptors are members of the neurotransmitter ligand-gated ion channels: they mediate neuronal inhibition on binding GABA. The effects of GABA on GABAA receptors are modulated by a range of therapeutically important drugs, including barbiturates, anaesthetics and benzodiazepines (BZs)
[8]
. The BZs are a diverse range of compounds, including widely prescribed drugs, such as librium and valium, and their interaction with GABAA receptors provides the most potent pharmacological means of distinguishing different GABAA receptor subtypes.

GABAA receptors are pentameric membrane proteins that operate GABA-gated chloride channels
[9]
. Eight types of receptor subunit have been cloned, with multiple subtypes within some classes: alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, rho 1-3 and theta
[10, 11]
. Subunits are typically 50-60kDa in size and comprise a long N-terminal extracellular domain, containing a putative signal peptide and a disulphide-bonded β structural loop; 4 putative transmembrane (TM) domains; and a large cytoplasmic loop connecting the third and fourth TM domains. Amongst family members, the large cytoplasmic loop displays the most divergence in terms of primary structure, the TM domains showing the highest level of sequence conservation
[12]
.

Most GABAA receptors contain one type of alpha and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1
[14]
, though in some cases other subunits such as epsilon or delta may replace gamma. The BZ binding site is located at the interface of adjacent alpha and gamma subunits; therefore, the type of alpha and gamma subunits present is instrumental in determining BZ selectivity and sensitivity. Receptors can be categorised into 3 groups based on their alpha subunit content and, hence, sensitivity to BZs: alpha 1-containing receptors have greatest sensitivity towards BZs (type I); alpha 2, 3 and 5-containing receptors have similar but distinguishable properties (type II); and alpha 4-and 6-containing assemblies have very low BZ affinity
[14]
. A conserved histidine residue in the alpha subunit of type I and II receptors is believed to be responsible for BZ affinity
[14]
.

A cDNA encoding the human GABAA receptor beta 2 subunit has been cloned and sequenced
[4]
. Expression of recombinant human GABAA receptors containing different beta subunits (beta 1, beta 2 or beta 3) in both transfected cells and Xenopus laevis oocytes, has revealed the influence of the beta subunit on the pharmacology of the receptor. For a number of benzodiazepine binding site compounds, a barbiturate, and several neurosteroids, neither the affinity nor the efficacy of the compounds is influenced by the type of beta subunit present in the receptor molecule
[4]
. These observations suggest that the beta subunit does not significantly influence the benzodiazepine, barbiturate, or steroid site pharmacologies of human GABAA receptor subtypes
[4]
.

References

1.Structure and gating of the glutamate receptor ion channel. Wollmuth LP, Sobolevsky AI. Trends Neurosci. 27, 321-8, (2004). View articlePMID: 15165736

2.Assembly and trafficking of nicotinic acetylcholine receptors (Review). Millar NS, Harkness PC. Mol. Membr. Biol. 25, 279-92, (2008). View articlePMID: 18446614

3.Molecular structure and function of the glycine receptor chloride channel. Lynch JW. Physiol. Rev. 84, 1051-95, (2004). PMID: 15383648

4.Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors. Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI. Mol. Pharmacol. 44, 1211-8, (1993). View articlePMID: 8264558

5.Structural features of the ligand-binding domain of the serotonin 5HT3 receptor. Yan D, Schulte MK, Bloom KE, White MM. J. Biol. Chem. 274, 5537-41, (1999). View articlePMID: 10026168

6.Determination of the tyrosine phosphorylation sites of the nicotinic acetylcholine receptor. Wagner K, Edson K, Heginbotham L, Post M, Huganir RL, Czernik AJ. J. Biol. Chem. 266, 23784-9, (1991). View articlePMID: 1721053

7.Generation of two forms of the gamma-aminobutyric acidA receptor gamma 2-subunit in mice by alternative splicing. Kofuji P, Wang JB, Moss SJ, Huganir RL, Burt DR. J. Neurochem. 56, 713-5, (1991). View articlePMID: 1846404

8.Structure and pharmacology of vertebrate GABAA receptor subtypes. Whiting PJ, McKernan RM, Wafford KA. Int. Rev. Neurobiol. 38, 95-138, (1995). PMID: 8537206

9.GABA(A) receptor subtypes: dissecting their pharmacological functions. Rudolph U, Crestani F, Mohler H. Trends Pharmacol. Sci. 22, 188-94, (2001). View articlePMID: 11282419

10.International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ. Pharmacol. Rev. 50, 291-313, (1998). View articlePMID: 9647870

11.theta, a novel gamma-aminobutyric acid type A receptor subunit. Bonnert TP, McKernan RM, Farrar S, le Bourdelles B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Brown N, Wafford KA, Whiting PJ. Proc. Natl. Acad. Sci. U.S.A. 96, 9891-6, (1999). View articlePMID: 10449790

12.Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH. Nature 338, 582-5, (1989). View articlePMID: 2538761

13.GABA(A) receptors: Subtypes provide diversity of function and pharmacology. Olsen RW, Sieghart W. Neuropharmacology (2008). PMID: 18760291

14.GABA(A)-receptor subtypes: a new pharmacology. Mohler H, Crestani F, Rudolph U. 1, 22-5, (2001). View articlePMID: 11712530

GO terms

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